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    EudraCT Number:2014-000336-42
    Sponsor's Protocol Code Number:D4191C00001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-07-04
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-000336-42
    A.3Full title of the trial
    A Phase III, Randomised, Double-blind, Placebo-controlled, Multi-centre, International Study of MEDI4736 as Sequential Therapy in Patients with Locally Advanced, Unresectable Non-Small Cell Lung Cancer (Stage III) Who Have Not Progressed Following Definitive, Platinum-based, Concurrent Chemoradiation Therapy (PACIFIC)
    Studio internazionale di Fase III, randomizzato, in doppio cieco, controllato con placebo, multicentrico su MEDI4736 come terapia sequenziale in pazienti con carcinoma polmonare non a piccole cellule localmente avanzato, non resecabile (Stadio III) che non hanno presentato progressione dopo radiochemioterapia concomitante e definitiva a base di platino (PACIFIC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase III Study of MEDI4736 as Sequential Therapy in Patients with Locally Advanced Non-Small Cell Lung Cancer
    Studio di fase III di MEDI4736 come terapia sequenziale in pazienti con carcinoma polmonare non a piccole cellule localmente avanzato
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberD4191C00001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstraZeneca AB
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca AB
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca AB
    B.5.2Functional name of contact pointInformation Centre
    B.5.3 Address:
    B.5.3.1Street AddressSödertälje
    B.5.3.2Town/ citySödertälje
    B.5.3.3Post codeSE 151 85
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMEDI4736
    D.3.2Product code MEDI4736
    D.3.4Pharmaceutical form Lyophilisate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMEDI4736
    D.3.9.1CAS number 1428935-60-7
    D.3.9.2Current sponsor codeMEDI4736
    D.3.9.3Other descriptive nameMEDI4736
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Locally Advanced, Unresectable Non-Small Cell Lung Cancer (Stage III)
    carcinoma polmonare non a piccole cellule localmente avanzato, non resecabile (stadio III)
    E.1.1.1Medical condition in easily understood language
    Non-Small Cell Lung Cancer
    carcinoma polmonare non a piccole cellule
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10066490
    E.1.2Term Progression of non-small cell lung cancer
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10029514
    E.1.2Term Non-small cell lung cancer NOS
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of MEDI4736 treatment compared with placebo in terms of OS and PFS
    Valutare l'efficacia del trattamento con MEDI4736 rispetto a placebo in termini OS e PFS
    E.2.2Secondary objectives of the trial
    - To further assess the efficacy of MEDI4736 compared with placebo in terms of: OS24, ORR, DoR, APF12, APF18, PFS2 and DSR
    - To assess the safety and tolerability profile of MEDI4736 compared with placebo
    - To assess symptoms and health-related quality of life in patients treated with MEDI4736 compared with placebo
    - Valutare ulteriormente l'efficacia di MEDI4736 rispetto a placebo in termini di: OS24, ORR, DoR, APF12, APF18, PFS2 e DSR
    - Valutare il profilo di sicurezza e tollerabilità di MEDI4736 rispetto al placebo
    - Esplorare i sintomi e la qualità della vita correlata alla salute nei pazienti trattati con MEDI4736 rispetto al placebo
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacogenetics Research
    Ricerca farmacogenetica
    E.3Principal inclusion criteria
    1. Provision of signed, written and dated informed consent prior to any study specific procedures
    2. Male or female aged 18 years or older
    3. Patients must have histologically- or cytologically-documented NSCLC who present with locally advanced, unresectable (Stage III) disease
    4. Patients must have received at least 2 cycles of platinum-based chemotherapy concurrent with radiation therapy.
    5. Patients must have not progressed following definitive, platinumbased, concurrent chemoradiation therapy.
    6. Patients must provide an archival tumour sample.
    7. Life expectancy ≥12 weeks
    8. World Health Organization (WHO) Performance Status of 0 or 1
    9. Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients.
    10. Adequate organ and marrow function
    1. Fornire un consenso informato scritto, firmato e datato prima di qualsiasi procedura specifica dello studio
    2. Pazienti di sesso maschile o femminile di età pari o superiore ai 18 anni
    3. I pazienti devono avere un NSCLC documentato istologicamente o citologicamente che si presenta con malattia localmente avanzata, non resecabile (stadio III) OPPURE
    4. I pazienti devono avere ricevuto almeno 2 cicli di chemioterapia a base di platino con radioterapia
    5. I pazienti non devono presentare progressione dopo la radiochemioterapia concomitante e definitiva a base di platino.
    6. I pazienti devono fornire un campione di tumore archiviato
    7. Aspettativa di vita ≥12 settimane
    8. Performance Status 0 oppure 1 secondo l’Organizzazione mondiale della sanità (OMS)
    9. Evidenza di stato post-menopausale o test di gravidanza sul siero o sulle urine negativo per le pazienti pre-menopausali. Le donne di età ≥50 anni saranno considerate post-menopausali se
    10. Funzione d’organo e midollare adeguata
    E.4Principal exclusion criteria
    1. Participation in another clinical study with an investigational product during the last 4 weeks
    2. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study
    3. Mixed small cell and non-small cell lung cancer histology
    4. Receipt of sequential chemoradiation therapy for locally advanced NSCLC
    5. Patients with locally advanced NSCLC who have progressed whilst receiving definitive platinum based, concurrent chemoradiation therapy
    6. Receipt of any immunotherapy, or investigational drug within 4 weeks prior to the first dose of study drug
    7. Current or prior use of immunosuppressive medication within 28 days before the first dose of study drug, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Systemic steroid administration required to
    manage toxicities arising from radiation therapy delivered as part of the chemoradiation therapy for locally advanced NSCLC is allowed.
    8. Prior exposure to any anti-PD-1 or anti-PD-L1 antibody
    9. Any unresolved toxicity CTCAE >Grade 2 from the prior
    chemoradiation therapy.
    10. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study drug may be included (eg, hearing loss) after consultation with the AstraZeneca/MedImmune medical monitor.
    11. Patients with any grade pneumonitis from prior chemoradiation therapy
    12. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment.
    13. Recent major surgery within 4 weeks
    14. Active or prior documented autoimmune disease within the past 2 years, except for: Vitiligo, Grave's disease, or psoriasis not requiring systemic treatment
    15. Active or prior documented inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis)
    16. History of primary immunodeficiency
    17. History of organ transplant that requires therapeutic
    18. History of hypersensitivity to MEDI4736 or any excipient
    19. Uncontrolled intercurrent illness
    20. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study drug.
    21. History of another primary malignancy within 5 years prior to starting study drug, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ and the disease under study
    22. Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
    23. Any condition that, in the opinion of the investigator, would interfere with evaluation of the study drug or interpretation of patient safety or study results.
    1. Partecipazione a un altro studio clinico con un prodotto sperimentale durante le ultime 4 settimane
    2. Arruolamento concomitante in un altro studio clinico, salvo qualora si tratti di uno studio clinico osservazionale (non interventistico) o del periodo di follow-up di uno studio interventistico
    3. Istologia mista di carcinoma polmonare non a piccole cellule e a piccole cellule
    4. Pazienti sottoposti a radiochemioterapia sequenziale per NSCLC localmente avanzato
    5. Pazienti con NSCLC localmente avanzato che hanno presentato progressione durante la radiochemioterapia concomitante e definitiva a base di platino
    6. Ricezione di qualsiasi immunoterapia o farmaco sperimentale nelle 4 settimane precedenti la prima dose di farmaco dello studio
    7. Uso concomitante o pregresso di farmaci immunosoppressori nei 28 giorni precedenti la prima dose di farmaco dello studio, con l’eccezione di corticosteroidi per via intranasale e inalatoria o corticosteroidi sistemici a dosi fisiologiche, che non devono superare i 10 mg/die di prednisone, o un corticosteroide equivalente. È consentita la somministrazione di un corticosteroide sistemico richiesta per gestire tossicità derivanti dalla radioterapia, somministrato come parte della radiochemioterapia per NSCLC localmente avanzato.
    8. Esposizione precedente a qualsiasi anticorpo anti-PD-1 o anti-PD-L1
    9. Qualsiasi tossicità non risolta di grado >2 secondo i Criteri comuni di terminologia per gli eventi avversi (Common Terminology Criteria for Adverse Events, CTCAE) derivante da una precedente radiochemioterapia.
    10. Pazienti con tossicità irreversibile che non si prevede ragionevolmente di esacerbare con il farmaco dello studio (ad es., perdita dell’udito) potranno essere inclusi previa consultazione con il responsabile del monitoraggio medico di AstraZeneca/MedImmune.
    11. Pazienti con polmonite di qualsiasi grado presente prima della radiochemioterapia
    12. Qualsiasi chemioterapia, immunoterapia, terapia biologica od ormonale concomitante per il trattamento del carcinoma.
    13. Intervento chirurgico maggiore recente nelle 4 settimane precedenti l’ingresso nello studio
    14. Malattia autoimmune attiva o pregressa documentata nei 2 anni precedenti. NOTA: I pazienti con vitiligine, malattia di Grave o psoriasi che non richiedono trattamento sistemico (negli ultimi 2 anni) non sono esclusi.
    15. Malattia intestinale infiammatoria attiva o pregressa documentata (ad es., morbo di Crohn, colite ulcerosa)
    16. Anamnesi di immunodeficienza primaria
    17. Anamnesi di trapianto di organo che richiede immunosoppressione terapeutica
    18. Anamnesi di ipersensibilità a MEDI4736 o a uno qualsiasi degli eccipienti
    19. Malattia intercorrente non controllata
    20. Ricezione di vaccino vivo attenuato nei 30 giorni precedenti l’ingresso nello studio o entro 30 giorni dalla ricezione del farmaco dello studio.
    21. Anamnesi di altra neoplasia maligna primaria nei 5 anni precedenti l’inizio del farmaco dello studio, eccetto carcinoma a cellule basali o squamose della pelle trattato adeguatamente o carcinoma della cervice in situ e malattia in studio
    22. Pazienti di sesso femminile in gravidanza, allattamento o pazienti di sesso maschile o femminile potenzialmente fertili che non utilizzano un metodo efficace di contraccezione
    23. Qualsiasi condizione che, a giudizio dello Sperimentatore, interferirebbe con la valutazione del farmaco dello studio o l’interpretazione dei risultati della sicurezza per il paziente o dei risultati dello studio.
    E.5 End points
    E.5.1Primary end point(s)
    Both Progression free survival (PFS) and Overall survival (OS) are co-primary endpoints.
    entrambe PFS Progression free survival (sopravvivenza senza progressione) e OS Overall survival (sopravvivenza complessiva) sono end-points coprimari
    E.5.1.1Timepoint(s) of evaluation of this end point
    OS - Overall Survival is defined as the time from the date of randomization until death due to any cause. Estimated to be from baseline up to 5 years.
    PFS - Progression-Free Survival is defined as the time from randomization until the date of objective disease progression or death. Estimated to be from baseline up to 5 years.
    - OS è definita come il tempo trascorso dalla data della randomizzazione alla data del decesso per qualsiasi causa. Si stima essere dal basale fino a 5 anni.
    - PFS è definita come il tempo trascorso dalla data di randomizzazione alla data di progressione oggettiva della malattia o al decesso. Si stima essere dal basale fino a 5 anni.
    E.5.2Secondary end point(s)
    - Proportion of patients alive at 24 months from randomization (OS24)
    - Objective response rate (ORR)
    - Proporzione di pazienti vivi a 24 mesi dalla randomizzazione (OS24)
    - ORR Objective response rate (Tasso di risposta obiettiva)
    E.5.2.1Timepoint(s) of evaluation of this end point
    - OS24: The proportion of patients alive at 24 months. Estimated to be from baseline up to 5 years.
    - ORR: Defined as the number (%) of patients with at least 1 visit response of CR (Complete response) or PR (Partial response) and will be based on all randomised patients who have measurable disease. Study data collection expected to last for approximately 3 years.
    - OS24: Proporzione di pazienti vivi a 24 mesi. Si stima essere dal basale fino a 5 anni.
    - ORR: definita come il numero (%) di pazienti con almeno 1 visita con risposta completa (CR) o parziale (PR) e si baserà su tutti i pazienti randomizzati che hanno una patologia misurabile. La raccolta dei dati dello studio è attesa durare circa 3 anni.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned15
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA118
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    European Union
    Hong Kong
    Korea, Republic of
    New Zealand
    Russian Federation
    South Africa
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
    La fine dello studio è definita come “l’ultima vista dell’ultimo soggetto in studio”.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 484
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 396
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state44
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 298
    F.4.2.2In the whole clinical trial 880
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Treatment from Day 1 for a maximum of 12 months or study drug withdrawal if this occurs earlier.
    Trattamento dal Giorno 1 per un massimo di 12 mesi o fino all’interruzione del farmaco in studio, in caso ciò avvenga prima
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-09-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-07-24
    P. End of Trial
    P.End of Trial StatusOngoing
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